A Comparison Between GalT−/−;hCD39;hCD55 and GalT−/−;hCD39;hCD46;hCD55;TBM Pig Kidneys Transplanted in Nonhuman Primates

Abstract

Because there is a shortage of donor kidneys, researchers are exploring the possibility of using genetically modified pig kidneys for transplantation. Approaches involving knockout of carbohydrate genes or knockin of protective proteins have been attempted to determine the best gene modifications. In this study, we utilized GalT−/−; hCD39;hCD55 and GalT−/−; hCD39;hCD46;hCD55;thrombomodulin (TBM) pigs for transplantation in nonhuman primates (NHPs). The NHPs survived for 4 weeks after kidney transplantation (4 WAT) from the GalT−/−; hCD39;hCD55 pig and for 6 WAT from the GalT−/−; hCD39;hCD46;hCD55;TBM pig. However, messenger RNA (mRNA) sequencing and immunohistochemistry analysis revealed that the 6 WAT kidney exhibited more severe apoptosis, inflammation, loss of renal function, and renal fibrosis than the 4 WAT kidney. These results indicate that additional knockin of complement regulator ( hCD46) and coagulation regulator ( TBM) is not enough to prevent renal damage, suggesting that improved immune suppression is needed for more prolonged survival.